Neurobiology of Alzheimer’s Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions

Raskin, Joel; Cummings, Jeffrey L.; Hardy, John; Schuh, Kory; Dean, Robert A.

doi:10.2174/1567205012666150701103107

Cited by 156 publications

(106 citation statements)

References 101 publications

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“…One useful source of information for early AD diagnosis is structural MRI, which can reveal abnormalities in a wide range of brain areas. Multiple studies have found structural MRI (sMRI), a useful diagnostic tool that can contribute to detecting AD-related modifications before the development of clinical symptoms (Raskin et al 2015;Xie et al 2015;Teipel et al 2015;Besson et al 2015;Goveas et al 2015). A different way in which sMRI can assist in early AD diagnosis is by providing data sets for a distinct group of recently developed analytical procedures involving advanced mathematical and statistical methods such as machine learning (Gorji and Haddadnia 2015;Klöppel et al 2008;Salvatore et al 2015;Zhan et al 2015) and graph theory, the formal study of networks (Supekar et al 2008;Stam et al 2009;He et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Graph analysis of structural brain networks in Alzheimer’s disease: beyond small world properties

2016

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Changes in brain connectivity in patients with early Alzheimer's disease (AD) have been investigated using graph analysis. However, these studies were based on small data sets, explored a limited range of network parameters, and did not focus on more restricted sub-networks, where neurodegenerative processes may introduce more prominent alterations. In this study, we constructed structural brain networks out of 87 regions using data from 135 healthy elders and 100 early AD patients selected from the Open Access Series of Imaging Studies (OASIS) database. We evaluated the graph properties of these networks by investigating metrics of network efficiency, small world properties, segregation, product measures of complexity, and entropy. Because degenerative processes take place at different rates in different brain areas, analysis restricted to sub-networks may reveal changes otherwise undetected. Therefore, we first analyzed the graph properties of a network encompassing all brain areas considered together, and then repeated the analysis after dividing the brain areas into two sub-networks constructed by applying a clustering algorithm. At the level of large scale network, the analysis did not reveal differences between AD patients and controls. In contrast, the same analysis performed on the two sub-networks revealed that small worldness diminished with AD only in the sub-network containing the areas of medial temporal lobe known to be heaviest and earliest affected. The second sub-network, which did not present significant AD-induced modifications of 'classical' small world parameters, nonetheless showed a trend towards an increase in small world propensity, a novel metric that unbiasedly quantifies small world structure. Beyond small world properties, complexity and entropy measures indicated that the intricacy of connection patterns and structural diversity decreased in both sub-networks. These results show that neurodegenerative processes impact volumetric networks in a non-global fashion. Our findings provide new quantitative insights into topological principles of structural brain networks and their modifications during early stages of Alzheimer's disease.

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Section: Introductionmentioning

confidence: 99%

Graph analysis of structural brain networks in Alzheimer’s disease: beyond small world properties

2016

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“…Interestingly, in the case of [ tangles are sparsely detectable in the hippocampus (Raskin et al, 2015). Other studies also suggested that GPCR function is altered during AD (Thathiah and De Strooper 2011), especially in the CA1…”

Section: Discussionmentioning

confidence: 97%

“…In addition to these protein aggregates, the progressive loss of neurons and multiple neurotransmitter systems impairment represent the pathological hallmark of Alzheimer's disease (Tampellini, 2015;Raskin et al, 2015). Although the loss of cholinergic fibers seems to be closely related to cognitive impairment, perturbations of other neurotransmitter systems may be involved in the pathophysiology of the disease.…”

Section: Introductionmentioning

confidence: 99%

Agonist and antagonist bind differently to 5-HT1A receptors during Alzheimer’s disease: A post-mortem study with PET radiopharmaceuticals

et al. 2016

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PET imaging studies using 5-HT 1A receptor radiotracers show a decreased density of this receptor in hippocampi of patients with Alzheimer's disease (AD) at advanced stages. However, current 5-HT 1A receptor radiopharmaceuticals used in neuroimaging are antagonists, thought to bind to 5-HT 1A receptors in different functional states (i.e., both the one which displays high affinity for agonists and is thought to mediate receptor activation, as well as the state which has low affinity for agonists).Comparing the PET imaging obtained using an agonist radiotracer, which binds selectively to functional receptors, with the PET imaging obtained using an antagonist radiotracer would therefore provide original information on 5-HT 1A receptor impairment during AD. Quantitative autoradiography using [

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“…The neurobiology of AD is very complex, involving numerous pathological changes, while cholinergic dysfunction is just one of them. 33) Here we are considering that to develop new anti-dementia drugs in the future, aiming at the BDNF system may be more effective than the cholinergic system, as the former is more related to consolidation of memory compared with the latter. As we have known, by now a lot of compounds have been found to have anti-dementia effects in rodents via enhancing the BDNF signaling cascade, like arabinoxylan, WY14643, P7C3, and so on.…”

Section: Discussionmentioning

confidence: 99%

SKF83959 Has Protective Effects in the Scopolamine Model of Dementia

Sheng

Zhang

Gao

et al. 2018

Biological & Pharmaceutical Bulletin

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Patients with Alzheimer's disease (AD) always have cognitive impairments. In this study we investigated whether 6-chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) has improvements on cognitive dysfunction. The scopolamine model of dementia was used to investigate the anti-amnesic activities of SKF83959, and then, Western blotting and pharmacological inhibitor were used to assay the anti-amnesic mechanisms of SKF83959. It was found that SKF83959 administration significantly improved the scopolamine-induced memory impairments in the passive avoidance task, Y-maze test, and Morris water maze task. Moreover, SKF83959 treatment significantly antagonized the down-regulating effects of scopolamine on brain-derived neurotrophic factor (BDNF) signaling cascade in the hippocampus, but not cortex. Importantly, the usage of K252a, a selective inhibitor of tyrosine kinase B (TrkB), significantly attenuated the protective effects of SKF83959 in the scopolamine model. Collectively, this study shows that SKF83959 has beneficial effects in the scopolamine model of dementia by modulation of hippocampal BDNF signaling, implying a novel and potential therapeutic agent for treating dementia in AD.Key words brain-derived neurotrophic factor; memory; scopolamine; SKF83959 As a world-wide neurodegenerative disease, Alzheimer's disease (AD) causes huge damage to our society.1) In clinical, patients with AD always have dementia, meaning the loss of memory.2,3) Dementia is very common in older persons, and leads to severe interference in occupational and social performance. Current researches have revealed that patients with AD have severe cholinergic dysfunction in the brain, [4][5][6] and some cholinergic antagonists, especially scopolamine, have been shown to induce memory impariments in rodents. 7) In contrast, some acetylcholinesterase inhibitors (AChEIs), such as donepezil, were developed for AD therapy in clinical. However, current AChEIs used clinically have various adverse effects including diarrhea, insomnia and vomiting, and their efficacy are not very good.8) Therefore, developing novel therapeutic agents to treat dementia in AD is very necessary.6-Chloro-7,8-dihydroxy-3-methyl-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) is one compound which belongs to benzazepine family and has been acknowledged as a selective D 1 -D 2 heteromer agonist. Until now, a lot of reports have been showing the effects of SKF83959 on the brain. For example, Wu et al. showed that SKF83959 has protective effects against neuroinflammation. 9)Chu et al. reported that SKF83959 has promoting effects on neuronal release of glutamate. 10) Zhang et al. found that SKF83959 administration has beneficial and reversing effects in the 6-hydroxy-dopamine (6-OHDA) model of Parkinson's disease. 11) We noticed that in 2014, Jiang et al. demonstrated the antidepressant effects of SKF83959 in mice which were mediated through activating the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (Tr...

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Neurobiology of Alzheimer’s Disease: Integrated Molecular, Physiological, Anatomical, Biomarker, and Cognitive Dimensions

Cited by 156 publications

References 101 publications

Graph analysis of structural brain networks in Alzheimer’s disease: beyond small world properties

Graph analysis of structural brain networks in Alzheimer’s disease: beyond small world properties

Agonist and antagonist bind differently to 5-HT1A receptors during Alzheimer’s disease: A post-mortem study with PET radiopharmaceuticals

SKF83959 Has Protective Effects in the Scopolamine Model of Dementia

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